Apparatus for tissue transport and preservation

ABSTRACT

Systems and methods of the invention generally relate to prolonging viability of bodily tissue, especially lung tissue, through the use of an expandable accumulator to maintain a constant pressure within the lumen of the organ even during external pressure fluctuations due to, for example, flight. Systems and methods may include prolonging donor organ viability in storage through the use of an organ container that mimics the geometry and orientation of the organ in vivo.

RELATED APPLICATIONS

This application is a divisional application of U.S. non-provisionalapplication Ser. No. 16/002795, filed Jun. 7, 2018, which applicationclaims the benefit of and priority to U.S. provisional patentapplication Ser. Nos. 62/516,581, filed Jun. 7, 2017, 62/584,330, filedNov. 10, 2017, and 62/650,610, filed Mar. 30, 2018, all of the contentsof which are incorporated by reference herein in their entirety.

TECHNICAL FIELD

The disclosure relates to systems and methods for the storage andtransportation of bodily tissue.

BACKGROUND

The current invention generally relates to devices, systems, and methodsfor extracorporeal preservation of bodily tissue. Extracorporealpreservation of bodily tissue is essential in transplant procedures sothat donor tissue can be transported to a recipient in a remotelocation. In order to provide the best graft survival rates, donortissues must be matched to appropriate recipients. Because of the suddennature of most tissue donation events, appropriate recipients must berapidly located and must be within a limited geographic area of thedonor. Time limitations on the extracorporeal viability of donor tissuecan lead to less than ideal tissue matching and, worse, wasted donortissue. Prolonging the viability of donor tissue can allow for bettermatching between donor tissue and recipients and, in turn, can increasegraft survival rates and increase availability of donor tissue to thegrowing waitlists of individuals in need of transplants.

The most prevalent current technique for preserving a bodily tissue fortransplantation is static cold storage. While hypothermic temperaturesdecrease the oxygen demand of the bodily tissue, the tissue's viabilityis still time-limited by insufficient oxygen levels to meet the tissue'sdecreased metabolic needs. Another known technique for preserving abodily tissue for transplantation includes the use of hypothermicperfusion devices that can perfuse the tissue with oxygenated perfusate,supplying additional oxygen to the tissue's cells and prolonging tissueviability. The portability of such known devices is limited, however,because such known devices are large and require a significant volume ofcompressed gas and electrical power. Furthermore, such known devices arevery complex, which can lead to increased manufacturing costs and higherfailure rates.

An additional limitation of hypothermic storage is the tendency to causeedema, or the accumulation of fluid within the bodily tissue. The levelof edema generally increases with the length of hypothermic storage,providing another limitation on the amount of time that a tissue can bestored and remain viable.

Because of the time limitations on tissue viability, even given modernhypothermic storage and perfusion techniques, tissue and organs areoften transported via air and, accordingly, subjected to pressurechanges associated with changes in altitude.

SUMMARY OF THE INVENTION

Systems and methods of the invention are directed to increasing donortissue viability during and after storage and transport. In particular,systems and methods relate to storage and transport of lungs. As notedabove, tissue transported by air may be subjected to changes in pressureassociated with increases and decreases in altitude during flight. Whilechanges in pressure may affect any tissue being transported, they can beparticularly harmful to lung tissue. In typical donor lung retrieval andpreparation, the donor lung is inflated with air and the trachea orbronchus is stapled to hold the air in the partially inflated lung andto keep preservation fluid out of the airways during storage andtransport. Unfortunately, this inflation occurs on the ground and, oncesubjected to decreases in air pressure from flights at high altitude,the pressure differential between the sealed lung airways andsurrounding preservation fluid and air can result in over inflation ofthe lung and damage to the tissue including rupturing of the alveoli orother air passages. Accordingly systems and methods of the invention maybe used to monitor and maintain a relatively constant pressure withindonor lungs during transport and storage while maintaining a desiredlevel of inflation. Systems and methods can accomplish those tasks whilemaintaining separation between the non-sterile airway environment andthe sterilized outer tissue surfaces and preservation fluid to helpprevent infection of the donor tissue or the transplant recipient.Expandable accumulators of the invention may have variable volume andmay include a gauge to indicate the volume of the accumulator. Incertain embodiments, the accumulator may be filled to a volume based onthe atmospheric pressure at the recovery site in order to compensate forvarious ambient pressures based on altitude or weather conditions indifferent locations. Methods may include adjusting the volume of theaccumulator based on the ambient pressure at the recovery site beforeorgan transport.

In certain embodiments, an expandable accumulator is coupled to theairways of the donor lung(s) and sealed in fluid communicationtherewith. The expandable accumulator may be more compliant than theairways of the donor lung such that the expandable accumulator expandsin response to a relative increase in the volume of gas (e.g., through achange in relative pressure) contained in the closed system formed bythe lungs airways and accumulator. By expanding, the accumulator canaccommodate and absorb the relative increases in gas volume, stabilizingpressure within the system, and preventing over-inflation of and damageto the lung tissue.

Another drawback of current lung transport techniques is that lungs aretypically transported horizontally on a flat surface or on a bed ofcrushed ice. Both techniques are far different from the geometry andorientation of the lung's anatomical home. By resting the lunghorizontally, gravity can crush or damage the bottom-most airways. Arough bed of crushed ice only complicates the issue. Accordingly,systems and methods of the invention may include replicating thegeometry of the chest cavity and/or the orientation of the lung thereinduring transport and storage of donor lungs. In certain embodiments, alung or pair of lungs may be placed horizontally on a smooth surfacewith a raised central saddle portion to replicate the spine.Alternatively, a lung or pair of lungs may be suspended in an uprightposition similar to the orientation of the lung in a standing humanbody. In such instances, the lung or lungs may be suspended by thetrachea or bronchus which may be secured to a support tube in fluidcommunication with, for example, an expandable accumulator as describedabove.

Systems and methods of the invention have application in both staticcold storage devices and hypothermic machine perfusion devices. Incertain embodiments, hypothermic machine perfusion devices areconfigured to oxygenate and perfuse a bodily tissue for extracorporealpreservation of the bodily tissue. In lung applications, the perfusatemay be pumped through the lung's vasculature and kept separate from theclosed airway-accumulator air system described above. The perfusionapparatuses can include a pneumatic system, a pumping chamber, and anorgan chamber. The pneumatic system may be configured for the controlleddelivery of fluid to and from the pumping chamber based on apredetermined control scheme. The predetermined control scheme can be,for example, a time-based control scheme or a pressure-based controlscheme. The pumping chamber is configured to diffuse a gas into aperfusate and to generate a pulse wave for moving the perfusate througha bodily tissue. The organ chamber is configured to receive the bodilytissue and the perfusate. The organ chamber is configured tosubstantially automatically purge excess fluid from the organ chamber tothe pumping chamber. The pumping chamber may be configured tosubstantially automatically purge excess fluid from the pumping chamberto an area external to the apparatus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a system including a contained bellows-type expandableaccumulator.

FIG. 2 shows a system including an exposed bellows-type expandableaccumulator.

FIG. 3 shows a system including a rolling diaphragm expandableaccumulator with a spring in compression providing expansion resistance.

FIG. 4 shows a system including a rolling diaphragm expandableaccumulator with a spring in tension providing expansion resistance.

FIG. 5 shows a system including a balloon-type expandable accumulator.

FIG. 6 shows a system including a contained bellows-type expandableaccumulator with a weight providing expansion resistance.

FIG. 7 shows a perfusion-type organ storage container with an expandableaccumulator providing pressure control for a lumen of a stored organ.

FIGS. 8A and 8B show an organ container with a raised central portion.

FIG. 9 shows a pair of lungs disposed on the raised central portion ofan organ container

FIGS. 10A and 10B show an organ adapter.

FIG. 11 shows an external view of a closed organ container with anaccumulator according to certain embodiments.

FIG. 12 shows an exploded view of an organ container with an accumulatoraccording to certain embodiments.

FIG. 13 shows a cross-sectional view of a closed organ container with anaccumulator according to certain embodiments.

FIG. 14 shows an external view of an open organ container with anaccumulator according to certain embodiments.

FIG. 15 shows an external view of an open organ container with anaccumulator and a support tray according to certain embodiments.

FIG. 16A shows a transverse cross-sectional view of an approximatelyempty accumulator according to certain embodiments.

FIG. 16B shows a lateral cross-sectional view of an approximately emptyaccumulator according to certain embodiments.

FIG. 17 shows a lateral cross-sectional view of an approximately halffull accumulator according to certain embodiments.

FIG. 18 shows a lateral cross-sectional view of an approximately fullaccumulator according to certain embodiments.

FIG. 19 shows an exploded view of an accumulator according to certainembodiments.

FIG. 20 shows a pressure vs. volume curve for an ex-vivo lung model.

FIG. 21 shows lung pressure and volume across a range of ambient(atmospheric) pressures during transit without an accumulator based onvarious atmospheric pressures at recovery.

FIG. 22 shows lung pressure and volume across a range of ambient(atmospheric) pressures during transit without an accumulator withrecovery at 1 atm.

FIG. 23 shows lung pressure and volume across a range of ambient(atmospheric) pressures during transit with a spring-based accumulatorbased on various atmospheric pressures at recovery.

FIG. 24 shows lung pressure and volume across a range of ambient(atmospheric) pressures during transit with a spring-based accumulatorwith recovery at 1 atm.

FIG. 25 shows lung pressure and volume across a range of ambient(atmospheric) pressures during transit with a weight-based accumulatorbased on various atmospheric pressures at recovery.

FIG. 26 shows lung pressure and volume across a range of ambient(atmospheric) pressures during transit with a weight-based accumulatorwith recovery at 1 atm.

DETAILED DESCRIPTION

Devices, systems and methods are described herein that are configuredfor extracorporeal preservation and transportation of bodily tissue.Specifically, devices for monitoring and stabilizing pressure withininflated lungs are described. Systems and methods can compensate forpressure changes resulting from, for example, increases and decreases inaltitude during air transport of the organ. By bleeding off andreturning excess gases, volumetric expansion of the lung (i.e.,over-inflation) may be prevented, avoiding damaging the organ which canresult in decreased organ viability and decreased survival rates fortransplant recipients. Additional aspects include contoured storage andtransport chambers that can replicate the in-vivo anatomical orientationand geometry for a given organ. For example, a pair of donor lungs maybe placed against a smooth, raised, central saddle designed to replicatethe spine that the lungs would be resting against in vivo. Organs, suchas lungs or hearts, may be suspended in an upright position to replicatethe organ's orientation in a standing human and to prevent tissue damagecaused by pressure from the organ's own weight resting on itself.

FIG. 1 illustrates a tissue preservation and transportation system 101according to certain embodiments. An organ adapter 107 is adapted to becoupled to the airways (e.g., by the trachea or bronchus) of a lung 103.The organ adapter 107 may comprise a lumen that, when the organ adapter107 is coupled to the lung 103, is in fluid communication with theairways of the lung 103.

The organ adapter 107 is coupled to an expandable accumulator 105 andthe lumen of the organ adapter 107 is in fluid communication with asealed interior volume of the expandable accumulator 105. The expandableaccumulator 105 may be coupled by a valve 109, to an inlet 113. Theinlet 113 has a lumen that, when the valve 109 is open, is in fluidcommunication with the interior volume of the expandable accumulator105, the lumen of the organ adapter 107, and the airways of the lung103. When the valve 109 is closed, the interior volume of the expandableaccumulator 105, the lumen of the organ adaptor 107, and the airways ofthe lung 103 form an air-tight, closed environment that is sealed fromthe outside environment including, for example, any preservation fluidpresent within the organ container 111. The organ container 111 mayinclude one or more boxes or bags configured to contain both the organand any preservation fluid (e.g., temperature regulated, oxygenatedfluid) in a sterilized environment. In preferred embodiments, the organis placed into one or more sterile bags or boxes. For example, a lungmay be placed in three concentric sterile bags fitted with athrough-the-bag-wall cannula leading into the trachea plug. The cannulamay include a filter for each bag (e.g., a 0.2-micron sterile filter).Accordingly, both the exterior surface and interior, pressure-dampenedlumen of the organ are surrounded by three sterile layers.

In various embodiments, the accumulator may have an interior volume(fully expanded) of about, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3,3.5, 4, 4.5, or more liters. In preferred embodiments, the accumulatorhas a fully expanded interior volume of about 1 liter.

System 101 is configured to permit gas to move back and forth betweenthe airways of the lung 103 through the lumen of the organ adapter 107,and into the interior volume of the expandable accumulator 105. When thevalve 109 is open, the system 101 is configured to permit gas flow fromthe inlet 113, through the valve 109, into the lumen of the organadaptor 107, and finally into the airways of the lung 103. The expansionresistance of the expandable accumulator 105 may be adjustable, fixed,or progressive.

The organ adapter 107 may be configured to substantially retain thebodily tissue (e.g., lung) with respect to the expandable accumulator105. The organ adapter 107 may be configured to permit movement of a gasfrom the expandable accumulator 105, into the airways of the lung 103,and back. The organ adapter 107 can be configured to be coupled to abodily tissue such as a lung 103. The organ adapter 107 can be coupledto the bodily tissue in any suitable manner For example, in someembodiments, the organ adapter 107 can configured to be sutured to thebodily tissue. In another example, the organ adapter 107 is coupleableto the bodily tissue via an intervening structure, such as silastic orother tubing. In some embodiments, at least a portion of the organadapter 107, or the intervening structure, is configured to be insertedinto the bodily tissue such as the lumen of a trachea, bronchus, orother air passage of a lung 103. For example, in some embodiments, thelumen of the organ adapter 107 (or a lumen of the intervening structure)is configured to be fluidically coupled to a lumen of the bodily tissuesuch as an air passage of the lung 103.

In various embodiments including the use of one or more sterile bags orother containers for the organ, the organ adapter may be contained in orintegral to the inner most sterile bag and coupled to athrough-the-bag-wall cannula that transverses each of the bags or othercontainers. The cannula, at the outer most bag or other container, mayinclude an adapter to be removably coupled to the accumulator in thesystems described herein. Accordingly, the bagged organ may be easilyand quickly connected to the accumulator and inflated during loading andeasily and quickly disconnected upon arrival at the transplantationsite.

In some embodiments, the organ adapter (or simply referred as theadapter) can be configured to support the bodily tissue when the bodilytissue is coupled to the adapter. For example, in some embodiments, theadapter can include a retention mechanism (not shown) configured to bedisposed about at least a portion of the bodily tissue and to helpretain the bodily tissue with respect to the adapter. The retentionmechanism can be, for example, a net, a cage, a sling, or the like. Insome embodiments, the system can include a basket (not shown) or othersupport mechanism configured to support the bodily tissue when thebodily tissue is coupled to the adapter or otherwise received in thesystem. The organ adapter may be rigidly coupled to an interior wall(e.g. a lid) of an organ container such that the organ may be suspendedvia its connection point to the adapter.

The portion of the adapter that is inserted into a lumen of the organmay include a series of tapered steps such that a distal end of theadapter portion is narrower than a proximal end. In this manner, theadapter is configured to be inserted into a range of lumen sizes.

The lumen may be secured or sealed to the organ adapter via any meansincluding elastic tension in the organ lumen itself or through the useof sutures, elastic band, or other securing mechanisms on the outside ofthe lumen applying pressure thereupon to form an air-tight seal betweenthe lumen of the organ and the lumen of the adapter.

The expandable accumulator is configured to expand to accept relativeincreases in gas volume within the closed system in response to pressuredifferential changes between the closed system and the surroundingenvironment (e.g., during flight). The interior volume of the expandableaccumulator should resist expansion with an opposing force that is lessthan that of the lung. Accordingly, decreases in internal pressure ofthe closed system due to decreases in the pressure of the surroundingenvironment (e.g. during flight) will be borne by the expandableaccumulator such that the pressure within the system drops withoutvolumetric expansion of the lung airways (which could cause tissuedamage or rupture the airways).

The expandable accumulator is configured to be in constant communicationwith the internal (closed system) pressure and the external (surroundingenvironment) pressure, and to establish a nearly-constant differentialbetween the two while having compliance higher than the lung'scompliance. The pressure differential is such that the internal pressureis greater than the environment pressure. The pressure differentialkeeps the lungs inflated. The pressure differential would commonly bereferred to as the gauge pressure. When the system is initiallyprepared, the external pressure may be 1 bar (absolute) and the internalpressure would be 1+x bar, absolute (where the x is a suitable valuechosen for best storage performance). The gauge pressure of the closedsystem is therefore x bar, and the differential pressure across the lungis also x bar. At a later time, in transport, the external pressure maybe 0.75 bar for instance due to airplane cabin pressure when in flight.The internal pressure would be 0.75+x bar, so the gauge pressure isagain x bar, as is the pressure across the lung. In this manner theexpandable accumulator maintains a nearly-constant pressure differentialacross the lung (from inside to outside).

In order to maintain the nearly-constant pressure differential theexpandable accumulator will have a very high compliance, for examplemuch higher than the lung compliance. In certain embodiments, the systemmay be configured to maintain about a 15 cm H₂O gauge pressure insidethe organ. The pressure may be fixed or may be tunable or adjustableusing variable weight, spring tension, or other means depending on theaccumulator mechanism. Pressure in the system may be set by filling thesystem to a desired fixed pressure or may be controlled using anadjustable accumulator which may be acted on by a computer based oninputs received from a pressure or other sensor as described below.

An inlet of the system may be used to add or remove a gas from the lumenof the organ (e.g., airways of a lung). For example, where donor lungsare at least partially inflated for storage and transport, a retrievedlung may be secured to an organ adapter as shown in FIGS. 1-6 . Theinlet may be then connected to a gas source such as a compressed airtank or a source of oxygen or another gas or combinations thereof. Incertain embodiments, the gas source may comprise a pump or bulb formanually filling the system with ambient air or other gas. The pump orbulb may be integral to the transport container and travel with thecontainer or may be used to establish pressure and removed after a valvelocated between the pump or bulb and the organ is closed. The valveconnecting the inlet to the closed system of the lung airways, lumen ofthe adapter, and interior volume of the expandable accumulator may thenbe opened and oxygen or another gas or mixture of gasses may then beallowed to flow into the closed system. In certain embodiments (e.g.,lung transport), gasses such as oxygen may damage the tissue and, assuch, the fill gas will be selected accordingly (e.g., ambient air). Theclosed system may be inflated to a desired pressure which may bemonitored with a pressure gauge or sensor located on the gas source oron the closed system. The pressure sensor may be electric and include awireless sender located on the closed system such that pressure may bewirelessly monitored from outside an organ transport container duringtransport.

During inflation, as gas is admitted to the system, both the lungs andthe expandable accumulator will inflate until reaching the desired gaugepressure (designated “x” above). As additional gas is thereafteradmitted, the gas would preferentially fill the expandable accumulatorgiven that component's higher compliance. When the expandableaccumulator is entirely filled, the pressure would begin to rise abovethe “x” target, and the system would not have any remaining capacity.Therefore, when the system is filled the volume of gas may be adjustedsuch that a movable element of the expandable accumulator rests at atarget position (for instance 25% of travel). Once the expandableaccumulator is at that target position, the valve can be closed and theclosed system is sealed and ready for transport.

Once the lung has been inflated to a desired pressure, the valve may beclosed, sealing off the closed system. The lung coupled to theexpandable accumulator by the organ adapter along with the closed valveand the inlet may be then be placed in an organ container for storage ortransport and may be at least partially submerged in a fluid such as apreservation fluid as known in the art. Examples of preservation fluidand static and perfusion-based tissue containers compatible with systemsand methods of the invention are described in U.S. application Ser. No.14/460,489, incorporated herein by reference.

The fill of the accumulator can be adjusted at organ recovery accordingto the local ambient (e.g. barometric) pressure. A smaller accumulatorwould thereby be able to work identically whether filled in Denver CO,or Boston Mass., whatever the weather conditions. The accumulator mayinclude a scale or other indicator in customary barometric pressureunits. An exemplary pressure indicator 1115 is shown in FIGS. 11, 14,15, and 19 . An ambient pressure sensor or meter may also be includedfor reading ambient pressure at recovery. The system may then be filleduntil the piston reaches a mark on the scale or indicator on theaccumulator that matches the local barometric pressure reading. If notadjusted to local pressure conditions, a larger accumulator may be used.

The expandable accumulator may be of any configuration that permitsexpansion of its interior volume with less resistance than that of thelung's airways. Examples of expandable accumulators are shown in FIGS.1-6 . Materials for transport and storage containers of the inventionmay be selected to reduce weight in key components such as theaccumulator. For example, accumulators such as the rolling diaphragmtypes depicted in FIGS. 3 and 4 may comprise a piston that slides withina cylinder to adjust volume to dampen pressure changes in the tissue.The piston or other accumulator components may be constructed oflightweight materials such as aluminum, plastics, or carbon fiber or maybe constructed with lightweight techniques including low materialthickness with structural bracing for example. Reducing the weight ormass of the moving pieces of the accumulator helps to minimize pressurechanges resulting from movement (e.g., tilting) of the container oraccumulator therein. Pressure generating force is thereby primarilyestablished by an accumulator spring and relatively unaffected bygravity.

The expandable accumulator 105 depicted in FIG. 1 comprises abellows-type interior bladder that permits expansion. The bellows may becontained within a shell that may be rigid to preserve an open interiorvolume into which the bellows can expand. The bellows may rely oninherent shape memory in the material of the bellows itself to provideresistance to expansion or may use, for example, springs opposing theexpansion of the bellows via compression or tension. Any known springtype may be used including coiled materials or elastic bands to provideexpansion resistance. The spring rate can be selected such that theexpansion resistance provided to the interior volume of the accumulatoris less than the expansion resistance of the lung's airways. Theexpansion resisting force may be a single rate or may be progressive oradjustable. The expansion resisting force can be modeled on theexpansion resistance profile of lung airways in order to better maintaina constant pressure within the lung. In various embodiments, a constantforce spring can be used to maintain internal pressure. Constant forcesprings are springs for which the force they exert over their range ofmotion is relatively constant. Constant force springs may be constructedfrom rolled ribbons of, for example, spring steel. In certainembodiments, the springs used in the systems depicted in FIGS. 3 and 4may be constant force springs. In some embodiments, a pair of constantforce springs may be used in a back-to-back orientation.

FIG. 2 shows a system 201 including a lung 203, an organ adapter 207, anexpandable accumulator 205, a valve 209, and an inlet 213 all placedwithin an organ container 211. The components are configured and relateto each other in a similar manner to that shown in FIG. 1 aside fromdifferences in the operation of the expandable accumulator 205. Theexpandable accumulator 205 comprises a bellows type accumulator 205 thatis not contained in a shell such that the outer surface of theexpandable accumulator 205 is in direct communication with the interiorenvironment of the organ container 211. The expandable accumulator 205may provide expansion resistance through its own material properties orthrough applied force from, for example, a spring.

FIG. 3 shows a system 301 including a lung 303, an organ adapter 307, anexpandable accumulator 305, a valve 309, and an inlet 313 all placedwithin an organ container 311. The components are configured and relateto each other in a similar manner to that shown in FIG. 1 aside fromdifferences in the operation of the expandable accumulator 305. Theexpandable accumulator 305 comprises a rolling diaphragm and a spring incompression to provide expansion resistance.

The rolling diaphragm contributes to a low-friction, low-hysteresisaccumulator advantageous to tissue preservation as described herein,especially in lung preservation and transport apparatuses. The diaphragmmay be constructed of any suitable material including latex, rubber, orsilicon.

FIG. 4 shows a system 401 including a lung 403, an organ adapter 407, anexpandable accumulator 405, a valve 409, and an inlet 413 all placedwithin an organ container 411. The components are configured and relateto each other in a similar manner to that shown in FIG. 3 aside fromdifferences in the operation of the expandable accumulator 405. Theexpandable accumulator 405 comprises a rolling diaphragm and a spring intension to provide expansion resistance.

A diaphragm-type accumulator system as exemplified in FIGS. 3 and 4 mayuse a constant force spring to maintain a constant internal pressure inthe lung or other organ. The diaphragm may be coupled to one or moresprings in tension, compression, or some combination thereof (e.g., twoopposing springs coupled to the diaphragm and providing expansionresistance through both compression and tension).

FIG. 5 shows a system 501 including a lung 503, an organ adapter 507, anexpandable accumulator 505, a valve 509, and an inlet 513 all placedwithin an organ container 511. The components are configured and relateto each other in a similar manner to that shown in FIG. 1 aside fromdifferences in the operation of the expandable accumulator 205. Theexpandable accumulator 505 comprises a balloon-type bladder whereinexpansion resistance is provided by the elasticity of the materialcomprising the walls of the expandable accumulator 505. As shown in FIG.5 , the lungs 503 are suspended in a vertical orientation from the organadapter 507 providing the benefits described above.

FIG. 6 shows a system 601 including a lung 603, an organ adapter 607, anexpandable accumulator 605, a valve 609, and an inlet 613 all placedwithin an organ container 611. The components are configured and relateto each other in a similar manner to that shown in FIG. 1 aside fromdifferences in the operation of the expandable accumulator 605. Theexpandable accumulator 105 depicted in FIG. 1 comprises a bellows-typeinterior bladder that permits expansion. The bellows may be containedwithin a shell that may be rigid to preserve an open interior volumeinto which the bellows can expand. The bellows may rely on inherentshape memory in the material of the bellows itself to provide resistanceto expansion or may use, for example, gravity to provide the expansionresistance through a weight 615 placed on top of the bellows.

As noted, systems of the invention are compatible with and may includeany static or perfusion-type preservation apparatus. An example of sucha configuration is shown in FIG. 7 . An apparatus 10 is shown configuredto oxygenate a perfusate (not shown) received in a pumping chamber 14 ofthe apparatus. The apparatus 10 includes a valve 12 configured to permita fluid (e.g., oxygen) to be introduced into a first portion 16 of thepumping chamber 14. A membrane 20 is disposed between the first portion16 of the pumping chamber 14 and a second portion 18 of the pumpingchamber. The membrane 20 is configured to permit the flow of a gasbetween the first portion 16 of the pumping chamber 14 and the secondportion 18 of the pumping chamber through the membrane. The membrane 20is configured to substantially prevent the flow of a liquid between thesecond portion 18 of the pumping chamber 14 and the first portion 16 ofthe pumping chamber through the membrane. In this manner, the membranecan be characterized as being semi-permeable.

The membrane 20 is disposed within the pumping chamber 14 along an axisAl that is transverse to a horizontal axis A2. Said another way, themembrane 20 is inclined, for example, from a first side 22 to a secondside 24 of the apparatus 10. As such, as described in more detail below,a rising fluid in the second portion 18 of the pumping chamber 14 willbe directed by the inclined membrane 20 towards a port 38 disposed atthe highest portion of the pumping chamber 14. The port 38 is configuredto permit the fluid to flow from the pumping chamber 14 into theatmosphere external to the apparatus 10. In some embodiments, the port38 is configured for unidirectional flow, and thus is configured toprevent a fluid from being introduced into the pumping chamber 14 viathe port (e.g., from a source external to the apparatus 10). In someembodiments, the port 38 includes a luer lock.

The second portion 18 of the pumping chamber 14 is configured to receivea fluid. In some embodiments, for example, the second portion 18 of thepumping chamber 14 is configured to receive a liquid perfusate. Thesecond portion 18 of the pumping chamber 14 is in fluid communicationwith an adapter 26. The adapter 26 is configured to permit movement ofthe fluid from the pumping chamber 14 to a bodily tissue T. For example,in some embodiments, the pumping chamber 14 defines an aperture (notshown) configured to be in fluidic communication with a lumen (notshown) of the adapter 26. The adapter 26 is configured to be coupled tothe bodily tissue T. The adapter 26 can be coupled to the bodily tissueT in any suitable manner For example, in some embodiments, the adapter26 is configured to be sutured to the bodily tissue T. In anotherexample, the adapter 26 is coupleable to the bodily tissue T via anintervening structure, such as silastic or other tubing. In someembodiments, at least a portion of the adapter 26, or the interveningstructure, is configured to be inserted into the bodily tissue T. Forexample, in some embodiments, the lumen of the adapter 26 (or a lumen ofthe intervening structure) is configured to be fluidically coupled to avessel of the bodily tissue T.

Where the tissue T is, for example a lung, the airways of the tissue Tmay be coupled to an expandable accumulator 705 and associated systemsas described herein via an organ adapter 707 (e.g., via the trachea orbronchus).

In some embodiments, the adapter 26 is configured to support the bodilytissue T when the bodily tissue T is coupled to the adapter. Forexample, in some embodiments, the adapter 26 includes a retentionmechanism (not shown) configured to be disposed about at least a portionof the bodily tissue T and to help retain the bodily tissue T withrespect to the adapter. The retention mechanism can be, for example, anet, a cage, a sling, or the like. In some embodiments, the apparatus 10includes a basket (not shown) or other support mechanism configured tosupport the bodily tissue T when the bodily tissue T is coupled to theadapter 26 or otherwise received in the apparatus 10.

An organ chamber 30 is configured to receive the bodily tissue T and afluid. In some embodiments, the apparatus 10 includes a port 34 that isextended through the apparatus 10 (e.g., through the pumping chamber 14)to the organ chamber 30. The port 34 is configured to permit fluid(e.g., perfusate) to be introduced to the organ chamber 30. In thismanner, fluid can be introduced into the organ chamber 30 as desired byan operator of the apparatus. For example, in some embodiments, adesired amount of perfusate is introduced into the organ chamber 30 viathe port 34, such as before disposing the bodily tissue T in the organchamber 30 and/or while the bodily tissue T is received in the organchamber. In some embodiments, the port 34 is a unidirectional port, andthus is configured to prevent the flow of fluid from the organ chamber30 to an area external to the organ chamber through the port. In someembodiments, the port 34 includes a luer lock. The organ chamber 30 maybe of any suitable volume necessary for receiving the bodily tissue Tand a requisite amount of fluid for maintaining viability of the bodilytissue T. In one embodiment, for example, the volume of the organchamber 30 is approximately 2 liters.

The organ chamber 30 is formed by a canister 32 and a bottom portion 19of the pumping chamber 14. In a similar manner as described above withrespect to the membrane 20, an upper portion of the organ chamber(defined by the bottom portion 19 of the pumping chamber 14) can beinclined from the first side 22 towards the second side 24 of theapparatus. In this manner, as described in more detail below, a risingfluid in the organ chamber 30 will be directed by the inclined upperportion of the organ chamber towards a valve 36 disposed at a highestportion of the organ chamber. The valve 36 is configured to permit afluid to flow from the organ chamber 30 to the pumping chamber 14. Thevalve 36 is configured to prevent flow of a fluid from the pumpingchamber 14 to the organ chamber. The valve 36 can be any suitable valvefor permitting unidirectional flow of the fluid, including, for example,a ball check valve.

The canister 32 can be constructed of any suitable material. In someembodiments, the canister 32 is constructed of a material that permitsan operator of the apparatus 10 to view at least one of the bodilytissue T or the perfusate received in the organ chamber 30. For example,in some embodiments, the canister 32 is substantially transparent. Inanother example, in some embodiments, the canister 32 is substantiallytranslucent. The organ chamber 30 can be of any suitable shape and/orsize. For example, in some embodiments, the organ chamber 30 can have aperimeter that is substantially oblong, oval, round, square,rectangular, cylindrical, or another suitable shape.

In use, the bodily tissue T is coupled to the adapter 26. The pumpingchamber 14 is coupled to the canister 32 such that the bodily tissue Tis received in the organ chamber 30. In some embodiments, the pumpingchamber 14 and the canister 32 are coupled such that the organ chamber30 is hermetically sealed. A desired amount of perfusate is introducedinto the organ chamber 30 via the port 34. The organ chamber 30 can befilled with the perfusate such that the perfusate volume rises to thehighest portion of the organ chamber. The organ chamber 30 can be filledwith an additional amount of perfusate such that the perfusate flowsfrom the organ chamber 30 through the valve 36 into the second portion18 of the pumping chamber 14. The organ chamber 30 can continue to befilled with additional perfusate until all atmospheric gas thatinitially filled the second portion 18 of the pumping chamber 14 risesalong the inclined membrane 20 and escapes through the port 38. Becausethe gas will be expelled from the pumping chamber 14 via the port 38before any excess perfusate is expelled (due to gas being lighter, andthus more easily expelled, than liquid), an operator of the apparatus 10can determine that substantially all excess gas has been expelled fromthe pumping chamber when excess perfusate is released via the port. Assuch, the apparatus 10 can be characterized as self-purging. Whenperfusate begins to flow out of the port 38, the apparatus 10 is in a“purged” state (i.e., all atmospheric gas initially within the organchamber 30 and the second portion 18 of the pumping chamber 14 has beenreplaced by perfusate). When the purged state is reached, the operatorcan close both ports 34 and 38, preparing the apparatus 10 foroperation.

Oxygen (or another suitable fluid, e.g., gas) is introduced into thefirst portion 16 of the pumping chamber 14 via the valve 12. A positivepressure generated by the introduction of oxygen into the pumpingchamber 14 causes the oxygen to be diffused through the semi-permeablemembrane 20 into the second portion 18 of the pumping chamber. Becauseoxygen is a gas, the oxygen expands to substantially fill the firstportion 16 of the pumping chamber 14. As such, substantially the entiresurface area of the membrane 20 between the first portion 16 and thesecond portion 18 of the pumping chamber 14 is used to diffuse theoxygen. The oxygen is diffused through the membrane 20 into theperfusate received in the second portion 18 of the pumping chamber 14,thereby oxygenating the perfusate.

In the presence of the positive pressure, the oxygenated perfusate ismoved from the second portion 18 of the pumping chamber 14 into thebodily tissue T via the adapter 26. For example, the positive pressurecan cause the perfusate to move from the pumping chamber 14 through thelumen of the adapter 26 into the vessel of the bodily tissue T. Thepositive pressure is also configured to help move the perfusate throughthe bodily tissue T such that the bodily tissue T is perfused withoxygenated perfusate.

After the perfusate is perfused through the bodily tissue T, theperfusate is received in the organ chamber 30. In this manner, theperfusate that has been perfused through the bodily tissue T is combinedwith perfusate previously disposed in the organ chamber 30. In someembodiments, the volume of perfusate received from the bodily tissue Tfollowing perfusion combined with the volume of perfusate previouslydisposed in the organ chamber 30 exceeds a volume (e.g., a maximum fluidcapacity) of the organ chamber 30. A portion of the organ chamber 30 isflexible and expands to accept this excess volume. The valve 12 can thenallow oxygen to vent from the first portion 16 of the pumping chamber14, thus, reducing the pressure in the pumping chamber 14. As thepressure in the pumping chamber 14 drops, the flexible portion of theorgan chamber 30 relaxes, and the excess perfusate is moved through thevalve 36 into the pumping chamber 14. The cycle of oxygenating perfusateand perfusing the bodily tissue T with the oxygenated perfusate can berepeated as desired.

FIGS. 8A and 8B show an organ container 811 comprising a smooth raisedportion 815 or saddle disposed on an interior wall of the organcontainer and designed to mimic the shape of the spine to replicate thein vivo environment of lungs being stored or transported. Such organcontainers 811 are compatible with any other systems described hereinincluding perfusing or static storage containers and various pressureregulating systems. FIG. 9 shows positioning of a pair of donor lungs915 on a raised center portion 915 of an organ container 911 intended tomimic the spine in the lungs' in vivo environment.

The interior of organ containers of the invention may contain a fixed orremovable shelf or tray configured to support cooling materials (e.g.,frozen gel packs). Such a tray allows the organ to be loaded into thecontainer before the tray is in place and, once the tray is inserted,the tray supports the cooling materials keeping them proximate to theorgan for cooling purposes but prevents the materials from contactingthe organ which can cause damage thereto. The tray may further serve tolocate the organ within the colder bottom portion of the container.

FIGS. 10A and 10B show an organ adapter 1007 configured for insertioninto the trachea of a donor lung to be transported using a tissuepreservation and transportation system as described above. The organadapter 1007 may taper as shown in FIGS. 10A and 10B to form anair-tight seal against the interior surface of the trachea or otherorgan opening to be transported and may include ridges 1017 to aidretention of the adapter 1007 within the organ opening once inserted.The organ adapter 1007 includes tubing 1015 for connecting to anexpandable accumulator as described above and includes an inner lumen1019 for providing fluid communication between the accumulator and theinterior of the organ. Once inserted into the organ, the organ adapter1007, interior space of the organ, and the accumulator form a closed,air-tight system.

Systems of the invention may include a variety of sensors configured tosense and report, for example, temperature of the tissue, temperature ofa preservation fluid or perfusate, pressure within the closed airsystem, pressure within the fluid, or ambient pressure. Displays for thesensors may be disposed on the outer surfaces of the organ transport ormay be wirelessly linked to the internal sensors.

In some embodiments, a temperature sensor may include a probe positionedin the transport cavity and attached by a flexible cable to atemperature datalogger. The probe may not be wetted (i.e., the probewould remain outside of any sterile bags or containers) and may besuspended in air by a bracket or support in order to avoid directcontact with any cooling materials. The probe would thereby recordand/or report the cavity temperature rather than the lung tissuetemperature.

In certain embodiments, the sensor may comprise a mechanical flag thatindicates the furthest expansion of the expandable accumulator and cantherefore indicate if the accumulator reached maximum expansionpresenting the possibility that additional pressure was absorbed by thelung tissue through over-inflation.

FIG. 11 shows an exemplary organ container 1101 with an accumulator 1105having an accumulator scale 1115 to indicate barometric pressure. Asnoted above, the indicator may be used by technicians when adjusting theaccumulator to local pressure conditions. The organ container 1101 mayinclude a recess, port, or other feature for retaining the accumulator1105, preferably, as shown in FIG. 11 , in a position that allows forexternal monitoring of the accumulator 1105. The organ container mayinclude wheels and an extendable handle as shown for ease of transportand storage.

FIG. 12 shows an exploded view of an exemplary organ container 1101. Theorgan container 1101 features an accumulator 1105, a gas source 1113(e.g., a bulb) for pressurizing the system, and an organ adapter 1107(e.g., a trachea plug) for interfacing an organ with the system. Theorgan container 1101 also includes tubing 1111 or connectors forcoupling the gas source 1113 and the organ adapter 1107 to theaccumulator 1105. The organ container 1101 may also use a valve 1109(e.g., a roller clamp) operable to regulate fluid communication betweenthe gas source 1113 and the accumulator 1105 by, for example, acting onthe tubing 1111.

FIG. 13 shows a cross-sectional view of an exemplary organ container1101 illustrating an exemplary configuration of various componentsdescribed herein including an accumulator 1105 an organ adapter 1107(not coupled to an organ) and connecting tubing 1111. A sensor 1117(e.g., a temperature sensor) as described above, is also included at thebottom of the organ camber and, while potentially wireless in someembodiments, is depicted in FIG. 13 in a wired format in electroniccommunication with an external display 1119 (e.g., an LCD screen) todisplay data obtained from the sensor 1117. An organ such as a lungwould rest on the bottom of the cavity.

FIG. 14 shows an external view of an open organ container 1101 with anaccumulator 1105 according to certain embodiments. With the lid removedfrom the exemplary organ container 1101, it is ready to accept ordeliver an organ. The accumulator 1105 with a pressure indicator 1115 isshown placed in a fitted receptacle on the organ container 1101. A gassource 1113 is connected by tubing 1111 to the accumulator 1105 and thatconnection is regulated by a valve 1109. The organ container 1101 alsofeatures a storage pocket 1121 for receiving and storing the gas source1113, valve 1109, and tubing 1111 when not in use. The illustrated organcontainer 1101 does not have an organ loaded and so the organ adapter1107 inside the cavity is seen.

FIG. 15 shows an external view of an open organ container 1101 with anaccumulator 1105 with pressure indicator 1115. A tray 1123 is adapted tobe positioned above a loaded organ in the cavity of the organ container1101 to hold cooling materials such as frozen gel packs off of the organtissue surface. The tray may be supported by, for example, indentions inthe interior walls of the cavity. The gas source 1113 is shown stored inthe storage pocket 1121 for transport.

FIG. 16A shows a transverse cross-sectional view of an approximatelyempty accumulator 1105 according to certain embodiments and FIG. 16Bshows a lateral cross-sectional view. The accumulator 1105 includes apiston 1125 and a rolling diaphragm 1127 as described above. As seen inFIG. 16B, a pair of back-to-back constant force springs 1129 comprisingrolled ribbons of, for example, spring steel.

FIG. 17 shows a lateral cross-sectional view of an approximately halffull accumulator 1105 and FIG. 18 shows a lateral cross-sectional viewof an approximately full accumulator 1105. As seen in FIGS. 16B-18 , asthe accumulator 1105 is filled or expands, the rolling diaphragm 1127unfolds while the ribbons of the constant force springs 1129 unwindthereby providing resistance against said expansion. As noted earlier,the rolling diaphragm 1127 helps maintain a seal between the outersurface of the piston 1125 and the inner wall of the accumulator 1105while minimizing friction between the two surfaces that might interferewith the expansion or operation of the accumulator 1105.

FIG. 19 shows an exploded view of an accumulator 1105. The outer barrelof the accumulator 1105 may be constructed of a material such aspolycarbonate plastic and is preferably transparent enough for theposition of the piston 1125 therein to be externally readable against apressure indicator 1115 on the accumulator 1105. For example, the topedge of the piston 1125 may align with a mark on the pressure indicator1115 to indicate a pressure setting. A clear outer barrel may also allowfor monitoring of the state of the piston 1125 within the accumulator1105 during transport to observe, for example, a maximum displacementthereof. FIG. 19 shows a pair of constant force springs 1129 and a pairof connectors 1131 configured to couple to tubing to provide fluidcommunication between the interior of the accumulator 1105 and a gassource and an organ via an organ adapter.

As one skilled in the art would recognize as necessary or best-suitedfor the systems and methods of the invention, systems and methods of theinvention may include computers that may include one or more ofprocessor (e.g., a central processing unit (CPU), a graphics processingunit (GPU), etc.), computer-readable storage device (e.g., main memory,static memory, etc.), or combinations thereof which communicate witheach other via a bus. Computers may include mobile devices (e.g., cellphones), personal computers, and server computers. In variousembodiments, computers may be configured to communicate with one anothervia a network in order to display image series or allow remote storage,viewing, or selection of images of a given series.

A processor may include any suitable processor known in the art, such asthe processor sold under the trademark XEON E7 by Intel (Santa Clara,Calif.) or the processor sold under the trademark OPTERON 6200 by AMD(Sunnyvale, Calif.).

Memory preferably includes at least one tangible, non-transitory mediumcapable of storing: one or more sets of instructions executable to causethe system to perform functions described herein (e.g., softwareembodying any methodology or function found herein); data (e.g.,portions of the tangible medium newly re-arranged to represent realworld physical objects of interest accessible as, for example, a pictureof an object like a motorcycle); or both. While the computer-readablestorage device can in an exemplary embodiment be a single medium, theterm “computer-readable storage device” should be taken to include asingle medium or multiple media (e.g., a centralized or distributeddatabase, and/or associated caches and servers) that store theinstructions or data. The term “computer-readable storage device” shallaccordingly be taken to include, without limit, solid-state memories(e.g., subscriber identity module (SIM) card, secure digital card (SDcard), micro SD card, or solid-state drive (SSD)), optical and magneticmedia, hard drives, disk drives, and any other tangible storage media.

Input/output devices according to the invention may include one or moreof a video display unit (e.g., a liquid crystal display (LCD) or acathode ray tube (CRT) monitor), an alphanumeric input device (e.g., akeyboard), any temperature, pressure, or other sensor described herein,a cursor control device (e.g., a mouse or trackpad), a disk drive unit,a signal generation device (e.g., a speaker), a touchscreen, a button,an accelerometer, a microphone, a cellular radio frequency antenna, anetwork interface device, which can be, for example, a network interfacecard (NIC), Wi-Fi card, or cellular modem, or any combination thereof.

One of skill in the art will recognize that any suitable developmentenvironment or programming language may be employed to allow theoperability described herein for various systems and methods of theinvention. For example, systems and methods herein can be implementedusing Perl, Python, C++, C#, Java, JavaScript, Visual Basic, Ruby onRails, Groovy and Grails, or any other suitable tool. For a computer, itmay be preferred to use native xCode or Android Java.

EXAMPLES Example 1 Modeling of Lung Pressure Changes During Transport

Lung volume and pressure conditions were modeled during transportwithout an accumulator, with a spring-based accumulator, and with aweight based accumulator (as described above). Since PV=nRT (ideal gaslaw) the trapped volume inside the lung will obey pV/T=constant or p_(f)V_(f)/T_(f)=p_(o) V_(o)/T_(o) where “o” refers to starting and “f” tofinal conditions.

P is the atmospheric pressure, absolute. p is the internal pressure,absolute, biased somewhat above P. V is the contained volume (lung,tubing, accumulator) T is the temperature in Kelvin.

For pressure the model defines and uses cmH₂O and atm (the SI unitstandard). Pressure measurements are absolute unless otherwise stated.

${{{cmH}\; 2O} \equiv {\frac{{gm} \cdot g}{{cm}^{2}}\mspace{14mu} 1\mspace{14mu}{atm}}} = {{1.033 \times {10^{3} \cdot {cmH}}\; 2O\mspace{14mu} 1\mspace{14mu}{atm}} = {14.696 \cdot {psi}}}$Ambient Condition Ranges:

Ambient Pressure (P) can range between the following (note that weathermeasurements are usually in inHg)1atm=29.921in_HgPatm_(min)=25.69in_Hg=0.899atmPatm_(max):=32.06in_Hg=1.071atmAltitude at recovery should be accounted for. For example, the typicalpressure in a city such as Denver, Colo. may be calculated as:

${{P_{atmosphere}(h)}\text{:}} = {{1\mspace{14mu}{{atm}\; \cdot {\exp\left( \frac{{{- g} \cdot 0.0289644}{\frac{kg}{mol} \cdot h}}{8.31447{\frac{J}{K \cdot {mol}} \cdot 288.15}\; K} \right)}}{P_{atmosphere}\left( {5280\mspace{14mu}{ft}} \right)}} = {0.826\; \cdot \;{atm}}}$The range of P_(o) is from ˜0.8 to ˜1.08 atm. Lung temperature (T) canrange between the following (assumes that recovery occurs in coldoperating rooms and transport is under not as cold conditions):T_(o_min):=2° C.=275.15K and T_(o_max):=65° F.=291.483KTravel Conditions:

To model transit conditions, it is assumed that T stays approximatelyconstant. Allowing T_(f) to rise to 8° C. is conservative. Extremes ofpressure will be seen in airplane cabins and is approximated as followsfor various aircraft (Cabin Pressure is typically measured in equivalentaltitude):

Regulatory Maximum=2400 m (p_(atmosphere)(2400 m)=0.752 atm)

Boeing 767=2100 m (p_(atmosphere)(2100 m)=0.780 atm) (typical of olderairliners)

Airbus A380=1868 m (p_(atmosphere)(1868 m)=0.801 atm)

Boeing 747-400=1572 m (p_(atmosphere)(1572 m)=0.830 atm)

So flight pressures can range from 0.752 up to 0.830 atm.

Range Values for Exploring Solution Space:

i:=0 . . . 50 (where i is the ambient pressure index); j:=0 . . . 2(where j is the initial conditions index for solutions of multiple casessimultaneously); P_(min):=0.75 atm and P_(max):=1.10 atm

${P_{{travel}_{1}}\text{:} = P_{\min}} + {\frac{\left( {P_{\max} - P_{\min}} \right)}{50} \cdot 1}$Lung Parameters:

The lung values used herein are taken from literature. The volumes at 40cmH₂O and above are extrapolated. The resulting interpolated lungpressure-volume model is large: volume is 4.74 liters at 15 cmH2O. Thepressure-volume model was scaled to establish a resting volume of 3.5 Lat 15 cmH2O.″

${Lung}_{p}:={{\begin{bmatrix}{- 20} \\{- 16} \\{- 12} \\{- 8} \\{- 4} \\0 \\4 \\8 \\12 \\16 \\20 \\24 \\28 \\32 \\36 \\40 \\50 \\60 \\70 \\85 \\100\end{bmatrix}{cm}\mspace{11mu} H\; 2O\mspace{11mu}{Lung}_{v}}:={\begin{bmatrix}0.600 \\0.635 \\0.670 \\0.695 \\0.710 \\0.815 \\1.100 \\2.400 \\3.900 \\4.600 \\5.040 \\5.250 \\5.370 \\5.470 \\5.500 \\5.525 \\5.543754952 \\5.557634961 \\5.567219684 \\5.572870767 \\5.574845677\end{bmatrix}L}}$

V_(rest):=3.5 L; P_(rest):=15 cmH₂O

LungV (p, P):=interp[1spline(Lung_(p), Lung_(v)), Lung_(p), Lung_(v),(p-P)]

LungV(P_(rest), 0 cmH2O)=4.474 L

Vlung_(max)=5 L (this simulates a volume constraint from a perfectlyrigid lung) The scaled, max-limited Lung Volume formula is then:

${V_{lung}\left( {p,P} \right)}{\text{:} = {\min\left( {{Vlung}_{\max}{Lung}\mspace{14mu}{{V\left( {p,P} \right)} \cdot \frac{V_{rest}}{{Lung}\mspace{14mu}{V\left( {P_{rest},{0{cmH}\; 2O}} \right)}}}} \right)}}$

(where =internal and P =external pressure, absolute)

A graph of the lung curve can be modeled using the following equation:

Δ Plung_(min): = min (Lung_(p)) = −20 ⋅ cmH 2OΔ Plung_(max): = max (Lung_(p)) = 100 ⋅ cmH 2O${\Delta\;{Plung}_{i}\text{:}} = {{\Delta\;{Plung}_{\min}} + {\frac{\left( {{\Delta\;{Plung}_{\max}} - {\Delta\;{Plung}_{\min}}} \right)}{50} \cdot i}}$

A graph of the target volume, pressure and target compliance can becreated as follows:

${K_{target}\text{:}} = \frac{200\mspace{14mu}{mL}}{{cmH}\; 2O}$${Target}\mspace{14mu}{Line}\mspace{14mu} Y\text{:} = \begin{pmatrix}{10\mspace{14mu} L} \\V_{rest} \\{{- 1}L}\end{pmatrix}$${{Target}\mspace{14mu}{Line}\mspace{14mu} X\text{:}} = \begin{bmatrix}{P_{rest} + \frac{\left( {{{Target}\mspace{14mu}{LineY}_{0}} - V_{rest}} \right)}{K_{target}}} \\P_{rest} \\{P_{rest} + \frac{\left( {{{Target}\mspace{14mu}{LineY}_{2}} - V_{rest}} \right)}{K_{target}}}\end{bmatrix}$

The curve of an ex-vivo lung model, volume vs. pressure is shown in FIG.20 . The target shown is a lung volume of 3.5 L at 15 cmH2O. The curveis taken from literature and scaled (on Yaxis) to pass through target.Values for pressure>36 cmH2O are extrapolated.

Accumulator parameters for the model were varied based on theaccumulator used as follows:

1) No Accumulator:

AccumPresent=0(When this is zero, there's no accumulator in the system).

Vacm1tr_(min)=50 mL Vacm1tr_(max)=1500.0 mL (These values represent thedesigned volume range)

$\begin{matrix}{{Vacmltr}_{recovery} = {\begin{pmatrix}1.000 \\0.350 \\0.050\end{pmatrix} \cdot L}} & \;\end{matrix}$(this is set by the recovery team, e.g. system is filled with air untilaccumulator is at the stipulated volume, which may vary based on ambientpressure at time/place of recovery)

${Kacmltr} = {400.0 \cdot \frac{mL}{{cmH}\; 2O}}$(Higher numbers here represent a weight-loaded design; lower numbersrepresent a spring-loaded design)ΔP_(acm1tr)=15·cmH2O

(This is the nominal accumulator pressure, at Vacm1tr_(recovery1), e.g.,when the piston is at the target volume for the nominal pressure case.It is set by the weight or spring)

${V_{acmltr}\left( {p,P} \right)}\text{:}{= {\max\left\lbrack {{Vacmltr}_{\min},{{{\min\left\lbrack {{Vacmltr}_{\max},{{Vacmltr}_{{recovery}_{1}} + \left. \quad{{Kacmltr}\left( {p - P - {\Delta P}_{acmltr}} \right)} \right\rbrack}} \right\rbrack}\mspace{79mu}{{Hacmltr}_{\max}\text{:}}} = {{20\mspace{14mu}{cm}\mspace{79mu}{{Hacmltr}_{\max}\text{:}}} = {{7.874\mspace{14mu}{in}\mspace{79mu}{{Dacltr}\text{:}}} = {\sqrt{\frac{4{Vacmltr}_{\max}}{\pi\;{Hacmltr}_{\max}}} = {{{9.772\; \cdot {cm}}\mspace{79mu}{Fspring}_{\max}\text{:}} = {{\Delta\; P_{acmltr}{\frac{\pi}{4} \cdot {Dacltr}^{2}}} = {{{2.48\; \cdot {lbf}}{Fspring}_{\max}\text{:}} = {{{Fspring}_{\min} + {\frac{\left( {{Vacmltr}_{\max} - {Vacmltr}_{\min}} \right)}{Kacmltr} \cdot \left( {\frac{\pi}{4} \cdot {Dacltr}^{2}} \right)}} = {{{3.08\; \cdot \;{lbf}}\mspace{79mu}{Kspring}\text{:}} = {\frac{{Fspring}_{\max} - {Fspring}_{\min}}{{Hacmltr}_{\max}} = {0.076\mspace{14mu} \cdot \frac{lbf}{in}}}}}}}}}}}}} \right.}}$

Hspring_(min):=1 in (This is the spring height at max compression)

${H_{{spring}_{free}}\text{:}} = {{{Hspring}_{\min} + {Hacmltr}_{\max} + \frac{{Fspring}_{\min}}{Kspring}} = {41.456\mspace{11mu} \cdot \;{in}}}$(This is the free height of the spring and not meaningful forweight-biased designs)2) Spring-Based Accumulator:

Parameters are same as for no accumulator above aside from thefollowing:

     Accum  Present = 1$\mspace{79mu}{{Kacmltr} = {350.0\frac{mL}{{cmH}\; 2O}}}$${{Fspring}_{\max}\text{:}} = {{{Fspring}_{\min} + {\frac{\left( {{Vacmltr}_{\max} - {Vacmltr}_{\min}} \right)}{Kacmltr} \cdot \left( {\frac{\pi}{4} \cdot {Dacltr}^{2}} \right)}} = {3.165\mspace{14mu} \cdot \mspace{11mu}{lbf}}}$$\mspace{79mu}{{{Kspring}\text{:}} = {\frac{{Fspring}_{\max} - {Fspring}_{\min}}{{Hacmltr}_{\max}} = {0.087\mspace{14mu} \cdot \;\frac{lbf}{in}}}}$${{Hspring}_{free}\text{:}} = {{{Hspring}_{\min} + {Hacmltr}_{\max} + \frac{{Fspring}_{\min}}{Kspring}} = {37.383\mspace{14mu} \cdot \mspace{11mu}{in}}}$3) Weight-Based Accumulator:

Parameters are same as for no accumulator above aside from the following

     Accum  Present = 1$\mspace{79mu}{{Vacmltr}_{recovery} = {\begin{pmatrix}0.900 \\0.300 \\0.010\end{pmatrix} \cdot L}}$$\mspace{79mu}{{Kacmltr} = {10000.0\frac{mL}{{cmH}\; 2O}}}$${{Fspring}_{\max}\text{:}} = {{{Fspring}_{\min} + {\frac{\left( {{Vacmltr}_{\max} - {Vacmltr}_{\min}} \right)}{Kacmltr} \cdot \left( {\frac{\pi}{4} \cdot {Dacltr}^{2}} \right)}} = {3.165\mspace{11mu} \cdot \;{lbf}}}$$\mspace{79mu}{{{Kspring}\text{:}} = {\frac{{Fspring}_{\max} - {Fspring}_{\max}}{{Hacmltr}_{\max}} = {{3.045x\; 10^{- 3}\frac{lbf}{in}{Hspring}_{free}\text{:}} = {{{Hspring}_{\min} + {Hacmltr}_{\max} + \frac{{Fspring}_{\min}}{Kspring}} = {823.427\mspace{11mu} \cdot {in}}}}}}$Initial Conditions:

$T_{o} = {{\begin{bmatrix}4 \\4 \\4\end{bmatrix}{^\circ}\mspace{14mu}{C.\mspace{14mu} P_{o}}} = {\begin{bmatrix}0.860 \\1.000 \\1.080\end{bmatrix}\mspace{14mu}{atm}}}$where P_(o) is the external environmental pressure.

The accumulator's behavior was used to determine P_(o) and V_(o), e.g.,the initial internal pressure volume at the above P_(o) and T_(o) givenall other parameters. The accumulator is filled to the target volume,which sets the internal pressure.

${{P_{o}\mspace{14mu}\text{:=}\mspace{14mu}{\frac{{Vacmltr}_{recovery}}{Kacmltr} \cdot 0}} + {\Delta\; P_{acmltr}} + P_{o}} = {{{{\begin{pmatrix}903.576 \\1048.227 \\1130.886\end{pmatrix} \cdot {cmH}}\; 2{Cp}_{o}} - P_{o}} = {{\begin{pmatrix}15 \\15 \\15\end{pmatrix} \cdot {cmH}}\; 2O}}$

The lung volume was determined by the initial and external pressures as:Vlung_(initial)=V_(lung)(p_(o), P_(o))=3.5L

The Contained Volume V_(o) is the sum of accumulator and lung volumes.This is the initial volume of air inside the system. This mass of airwill remain unchanged, so the ideal gas law governs its subsequentbehavior (relationship of pressure to volume). V_(o) can be defined asfollows for the various accumulator types:

No Accumulator:

${{V_{o}\mspace{14mu}\text{:=}\mspace{14mu}{{AccumPresent} \cdot {Vacmltr}_{recovery}}} + {Vlung}_{initial}} = {\begin{pmatrix}3.500 \\3.500 \\3.500\end{pmatrix}L}$Spring-Based Accumulator:

${{V_{o}\mspace{14mu}\text{:=}\mspace{14mu}{{AccumPresent} \cdot {Vacmltr}_{recovery}}} + {Vlung}_{initial}} = {\begin{pmatrix}4.500 \\3.850 \\3.550\end{pmatrix}L}$Weight-Based Accumulator:

${{V_{o}\mspace{14mu}\text{:=}\mspace{14mu}{{AccumPresent} \cdot {Vacmltr}_{recovery}}} + {Vlung}_{initial}} = {\begin{pmatrix}4.400 \\3.800 \\3.510\end{pmatrix}L}$

The equation for final volume Vf is based on the ideal gas law forcontained volume,

$\frac{p_{f} \cdot V_{f}}{T_{f}} = \frac{p_{o} \cdot V_{o}}{T_{o}}$solved for Vf:

$V_{f} = {\frac{p_{o} \cdot V_{o}}{T_{o}} \cdot \frac{T_{f}}{p_{f}}}$

The adapted equation was used in the solve function below:P_(guess):=1.2·p_(o) ₂given:

${\frac{{po} \cdot {Vo}}{To} \cdot \frac{Tf}{p_{guess}}} = {{{AccumPresent} \cdot {V_{acmltr}\left( {p_{guess},{Ptravel}} \right)}} + {V_{lung}\left( {p_{guess},{Ptravel}} \right)}}$with the following constraint added:P_(guess)>Ptravelproviding a solution of:ptravel(po, Vo, To, Tf, Ptravel):=Find)p_(guess))

The inputs to this function are the initial conditions together withtravel pressure and temperature. The output of this function is theinternal pressure.

The solution for a defined range of conditions can then be found:p_(travel) _(i,j) =ptravel(p_(o) _(j) ,V_(o) _(j) ,T_(o) _(j) ,T_(f),P_(travel) _(i) )Vlung_(travel) _(i,j) =V_(lung)(p_(travl) _(i,j) ,p_(travel) _(i) )Vacmltr_(travel) _(i,j) =AccumPresent V_(acm1tr)(P_(travel) _(i,j) ,P_(travel) _(i) )ΔP_(lung) _(i,j) =ptravel_(i,j)=P_(travel) _(i)

FIGS. 21 and 22 show lung pressure and volume in no-accumulator systemsgiven various parameters. Lung pressure and volume were plotted in FIG.21 given the following:

Initial conditions:

$P_{o} \equiv {\begin{pmatrix}{.86} \\1 \\1.08\end{pmatrix}1\mspace{14mu}{atm}\mspace{14mu}\begin{matrix}{Atmospheric} \\{{{Pressure}\mspace{14mu}{at}}\mspace{20mu}} \\{{Recovery}\mspace{34mu}}\end{matrix}}$ $T_{o} \equiv {\begin{pmatrix}4 \\4 \\4\end{pmatrix}{^\circ}\mspace{14mu}{C.\mspace{14mu}\begin{matrix}{{Internal}\mspace{79mu}} \\{{Temperature}\mspace{14mu}{at}} \\{{Recovery}\mspace{65mu}}\end{matrix}}}$Lung parameters:

-   -   Vlung_(max)=5L    -   limiting bag/box voume        Accumulator design parameters:

AccumPresent ≡ 0  (0 = no  accum)${Kacmltr} \equiv {400 \cdot \frac{mL}{{cmH}\; 2O}}$Realistic  spring ∼ 400  mL/cmH 2O.Weighted  piston > 5000  mL/cmH 2OΔ P_(acmltr) ≡ 15  cmH 2O  recovery  pressureVacmltr_(max) ≡ 1.5  L  maximum  volume${Vacmltr}_{\min} \equiv {50\mspace{14mu}{mL}\mspace{14mu}{minimum}\mspace{14mu}{volume}{Vacmltr}_{recovery}} \equiv {\begin{pmatrix}{1000\mspace{14mu}{mL}} \\{350\mspace{14mu}{mL}} \\{50\mspace{14mu}{mL}}\end{pmatrix}\mspace{14mu}\begin{matrix}{{{Accum}.}\mspace{65mu}} \\{{volume}\mspace{14mu}{as}\mspace{14mu}{set}} \\{{{by}\mspace{14mu}{recovery}}\mspace{20mu}} \\{{team}\mspace{95mu}}\end{matrix}}$In-transit temperature:

-   -   T_(f)=8° C.        Airplane cabin pressures:    -   Regulatory Minimum=0.75 atm    -   Older Airplanes=0.78 atm    -   Newer Airplanes=0.80-0.83 atm

Given the above values, FIG. 21 shows lung pressure and volume across arange of ambient (atmospheric) pressures during transit without anaccumulator based on three different atmospheric pressures at recovery(0.86 atm, 1 atm, and 1.08 atm). Lung volume, recovery at 0.86 Patm1201, lung volume, recovery at 1 Patm 1202, lung volume, recovery at1.08 Patm 1203, and accumulator volume 1207 (set to zero here torepresent a lack of accumulator) are plotted against the left handscale. Lung pressure, recovery at 0.86 Patm 1204, lung pressure recoveryat 1 Patm 1205, and lung pressure, recovery at 1.08 Patm 1206 areplotted against the right hand scale.

FIG. 22 shows lung pressure and volume across a range of ambient(atmospheric) pressures during transit without an accumulator withrecovery at 1 atm. The values are the same as given for the nominal (1atm recovery pressure) plot in FIG. 21 .

As shown in FIGS. 21 and 22 , the lung volume and pressure vary markedlyin response to changes in the in-transit ambient pressure from airplaneascent and descent. These changes can cause damage to the lung tissueand negatively impact viability of the organ for transplant.

FIGS. 23 and 24 show lung pressure and volume in spring-basedaccumulator systems given various parameters. Lung pressure and volumewere plotted in FIG. 23 given the following:

Initial Conditions:

$P_{o} \equiv {\begin{pmatrix}{.86} \\1 \\1.08\end{pmatrix}1\mspace{14mu}{atm}\mspace{14mu}\begin{matrix}{Atmospheric} \\{{{Pressure}\mspace{14mu}{at}}\mspace{20mu}} \\{{Recovery}\mspace{34mu}}\end{matrix}}$ $T_{o} \equiv {\begin{pmatrix}4 \\4 \\4\end{pmatrix}{^\circ}\mspace{14mu}{C.\mspace{14mu}\begin{matrix}{{Internal}\mspace{79mu}} \\{{Temperature}\mspace{14mu}{at}} \\{{Recovery}\mspace{59mu}}\end{matrix}}}$Lung Parameters:

-   -   Vlung_(max)=5 L        Accumulator Design Parameters:

AccumPresent ≡ 1  (0 = no  accum.)${Kacmltr} \equiv {350 \cdot \frac{mL}{{cmH}\; 2O}}$Realistic  spring ∼ 400  mL/cmH 2O.Weighted  piston > 5000  mL/cmH 2OΔ P_(acmltr) ≡ 15  cmH 2O  recovery  pressureVacmltr_(max) ≡ 1.5  L  maximum  volume${Vacmltr}_{\min} \equiv {50\mspace{14mu}{mL}\mspace{14mu}{minimum}\mspace{14mu}{volume}{Vacmltr}_{recovery}} \equiv {\begin{pmatrix}{1000\mspace{14mu}{mL}} \\{350\mspace{14mu}{mL}} \\{50\mspace{14mu}{mL}}\end{pmatrix}\mspace{14mu}\begin{matrix}{{{Accum}.}\mspace{65mu}} \\{{volume}\mspace{14mu}{as}\mspace{14mu}{set}} \\{{{by}\mspace{14mu}{recovery}}\mspace{20mu}} \\{{team}\mspace{95mu}}\end{matrix}}$In-transit temperature:

-   -   T_(f)=8° C.        Airplane cabin pressures:

Regulatory Minimum=0.75 atm

Older Airplanes=0.78 atm

Newer Airplanes=0.80-0.83 atm

Given the above values, FIG. 23 shows lung pressure and volume across arange of ambient (atmospheric) pressures during transit with aspring-based accumulator based on three different atmospheric pressuresat recovery (0.86 atm, 1 atm, and 1.08 atm). Lung volume, recovery at0.86 atm, 1 atm, and 1.08 atm 1401 and accumulator volume 1407 areplotted against the left hand scale. Lung pressure, recovery at 0.86atm, 1 atm, and 1.08 atm 1406 are plotted against the right hand scale.Of note compared to FIG. 21 , the lung volume, lung pressure, andaccumulator volume curves are consistent across the various atmosphericpressure conditions at recovery because the accumulator volume set atthe time of recover compensates for these differences. Furthermore, asshown in FIGS. 23-26 , the lung volume and lung pressure curves are muchflatter than those in FIGS. 21 and 22 (without an accumulator) while theaccumulator volume changes to offset pressure differentials caused bychanges in cabin pressure.

FIG. 24 shows lung pressure and volume across a range of ambient(atmospheric) pressures during transit without an accumulator withrecovery at 1 atm. The values are the same as given for the nominal (1atm recovery pressure) plot in FIG. 23 .

FIGS. 25 and 26 show lung pressure and volume in weight-basedaccumulator systems given various parameters. Lung pressure and volumewere plotted in FIG. 25 given the following:

Initial Conditions:

$P_{o} \equiv {\begin{pmatrix}{.86} \\1 \\1.08\end{pmatrix}1\mspace{14mu}{atm}\mspace{14mu}\begin{matrix}{Atmospheric} \\{{{Pressure}\mspace{14mu}{at}}\mspace{20mu}} \\{{Recovery}\mspace{34mu}}\end{matrix}}$ $T_{o} \equiv {\begin{pmatrix}4 \\4 \\4\end{pmatrix}{^\circ}\mspace{14mu}{C.\mspace{14mu}\begin{matrix}{{Internal}\mspace{79mu}} \\{{Temperature}\mspace{14mu}{at}} \\{{Recovery}\mspace{59mu}}\end{matrix}}}$Lung Parameters:

-   -   Vlung_(max)=5 L limiting bag/box volume        Accumulator Design Parameters:    -   Vlung_(max)=5 L limiting bag/box volume        Accumulator Design Parameters

AccumPresent ≡ 1  (0 = no  accum.)${Kacmltr} \equiv {10000 \cdot \frac{mL}{{cmH}\; 2O}}$Realistic  spring ∼ 400  mL/cmH 2O.Weighted  piston > 5000  mL/cmH 2OΔ P_(acmltr) ≡ 15  cmH 2O  recovery  pressureVacmltr_(max) ≡ 1.5  L  maximum  volume${Vacmltr}_{\min} \equiv {50\mspace{14mu}{mL}\mspace{14mu}{minimum}\mspace{14mu}{volume}{Vacmltr}_{recovery}} \equiv {\begin{pmatrix}{900\mspace{14mu}{mL}} \\{300\mspace{14mu}{mL}} \\{10\mspace{14mu}{mL}}\end{pmatrix}\mspace{14mu}\begin{matrix}{{{Accum}.}\mspace{65mu}} \\{{volume}\mspace{14mu}{as}\mspace{14mu}{set}} \\{{{by}\mspace{14mu}{recovery}}\mspace{20mu}} \\{{team}\mspace{95mu}}\end{matrix}}$In-transit temperature:

T_(f)=8° C.

Airplane cabin pressures:

-   -   Regulatory Minimum=0.75 atm    -   Older Airplanes=0.78 atm    -   Newer Airplanes=0.80-0.83 atm

Given the above values, FIG. 25 shows lung pressure and volume across arange of ambient (atmospheric) pressures during transit with aweight-based accumulator based on three different atmospheric pressuresat recovery (0.86 atm, 1 atm, and 1.08 atm). Lung volume, recovery at0.86 atm, 1 atm, and 1.08 atm 1601 and accumulator volume 1607 areplotted against the left hand scale. Lung pressure, recovery at 0.86atm, 1 atm, and 1.08 atm 1606 are plotted against the right hand scale.As with FIG. 23 , the lung volume, lung pressure, and accumulator volumecurves are consistent across the various atmospheric pressure conditionsat recovery because the accumulator volume, set at the time of recovercompensates for these differences. The lung volume and pressure curvesare slightly flatter than the spring-based accumulator curves in FIG. 23.

FIG. 26 shows lung pressure and volume across a range of ambient(atmospheric) pressures during transit without an accumulator withrecovery at 1 atm. The values are the same as given for the nominal (1atm recovery pressure) case in the plot in FIG. 25 .

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

EQUIVALENTS

Various modifications of the invention and many further embodimentsthereof, in addition to those shown and described herein, will becomeapparent to those skilled in the art from the full contents of thisdocument, including references to the scientific and patent literaturecited herein. The subject matter herein contains important information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and equivalents thereof.

What is claimed is:
 1. A method for storage of an organ, the methodcomprising: providing an organ container comprising: an expandableaccumulator comprising an expandable inner volume; and an organ adaptercomprising a lumen in fluid communication with the expandable innervolume and configured to be coupled to a lumen of an organ to form aclosed air system between the expandable inner volume and the lumen ofthe organ, wherein the expandable accumulator has an expansionresistance that is less than the expansion resistance of the lumen ofthe organ, such that the expandable inner volume is operable to expandand contract in response to changes in ambient pressure to maintain adesired pressure differential between the lumen of the organ and avariable ambient pressure and coupling the lumen of an organ to theorgan adapter.
 2. The method of claim 1, wherein the organ is one ormore lungs and the lumen of the organ is selected from the groupconsisting of a trachea or bronchus of the one or more lungs.
 3. Themethod of claim 1, wherein the organ container further comprises aninlet comprising a lumen and coupled to the expandable accumulator by aninlet valve such that the lumen of the inlet is in fluid communicationwith the lumen of the organ when the inlet valve is opened and theclosed air system between the expandable inner volume and the lumen ofthe organ is formed when the inlet valve is closed, the method furthercomprising; coupling a gas source to the inlet; opening the inlet valve;filling the lumen of the organ with gas from the gas source to a desiredpressure; closing the inlet valve; removing the gas source from theinlet; and closing the organ container with the organ disposed therein.4. The method of claim 1, wherein the expansion resistance of theexpandable accumulator is adjustable.
 5. The method of claim 2, whereinthe organ container further comprises a raised central portionconfigured to be placed against an organ within the organ container, themethod further comprising disposing the one or more lungs against theraised central portion.
 6. The method of claim 1, wherein the expandableaccumulator comprises a bellows.
 7. The method of claim 1, wherein theexpandable accumulator comprises a weight that provides the expansionresistance of the expandable accumulator.
 8. The method of claim 1,wherein the expandable accumulator comprises a spring that provides theexpansion resistance of the expandable accumulator.
 9. The method ofclaim 1, wherein the expandable accumulator comprises an expandablebladder comprising an elastic material wherein the elastic materialprovides the expansion resistance of the expandable accumulator.
 10. Themethod of claim 1, wherein the expandable accumulator comprises arolling diaphragm.
 11. The method of claim 1, wherein the expandableaccumulator has an adjustable volume, the method further comprisingadjusting the volume of the expandable accumulator based on ambientpressure when coupling the lumen of the organ to the organ adapter.